DD286354A5 - PROCESS FOR PREPARING SUBSTITUTED 2-CARBAMOYL-METHYL-4-PHENYL-1,2,5,6-TETRAHYDRO- AND 1,2-DIHYDRO-1-OXO-PYRIDAZINE - Google Patents

Abstract

The invention relates to a process for the preparation of substituted * and 1,2-dihydro-1-oxo-pyridazines with different substituents on the phenyl ring starting from various substituted * or 1,2-dihydro-1-oxo-pyridazines. The compounds have surprisingly antianaphylactic and nootropic action. Formula I * * * * Aminolysis of carboxylic acid esters; carboxylic acid amides; Antianaphylactic and nootropic compounds potential drugs}

Description

-CH _x -CO-OR ⁶

where R ³ , R ⁴ , R ⁶ or R ⁴ and R ^{6 have} the abovementioned meaning and R ⁶ = lower alkyl C ₁ -C ₄ and the dashed line is an optional double bond, with a corresponding amine at different temperatures, usually the boiling point of the amine, treated for different periods of time.

Process according to claim 1, characterized in that compounds of general formula II in a lower alkanol, preferably C ₁ -C ₄ , are mixed with dried ammonia gas and heated.

3. The method according to claim 1 and 2, characterized in that compounds of the general formula II are treated with aqueous ammonia solution at preferably room temperature.

Field of application of the invention

The invention relates to a process for the preparation of substituted 2-carbamoyl-methyl-4-phenyl-1,2,5,6-tetrahydro- and 1,2-dihydro-1-oxo-pyridazines of the general formula I. Such substances are surprisingly antianaphylactic and nootropic potential drugs.

-2- 286 354 Characteristic of the known state of the art

Compounds of general formula I are described neither in the patent nor in the chemical literature.

It has already been proposed that antianaphylactically active 2-carbalkoxymethyl-4-phenyl-1,2,5,6-tetrahydro-i-oxopyridazines and also 2-carbalkoxymethyl-4-phenyl-1,2-dihydro-1 oxo-phthalazines from ß-Benzoylpropion- or ß-Benzoylbenzoesäuren and a-Hydrazinoessigsäurealkylestersalze.n be prepared in a synthesis step.

In a Romanian patent (Cilianu-Bibian, S., A.Cirstea, M. Petrovanu, E.Rucinschi, I.Drutä, M.Caprosu, I. Ciocoiu and M.Mihalcea, Rome Ro 87,512 [CI.C07D 237/14 ], Sep. 30, 1985, Appl., 112, 805, 09 Dec, 1983) 2-carbaraoyl prepared by reacting 4- (4-bromophenyl) -1,2-dihydro-1-oxopyridazine with α-bromoacetic acid amide in equiv -methyl-4- (4-bromophenyl) -1,2-dihydro-1-oxopyridazine and its anticonvulsant activity.

A Japanese patent (Morishita Pharm KK 02.09.79-JA-034850 [11.09.80], C07D-237/04, C07D-409/04) involves the preparation of anti-hyperacid and anti-ulcer 2-tri-carbamoyl-methyl-4-phenyl-1 , 2-di- or 1,2,5,6-tetrahydro-1-oxopyridazine from the corresponding 2-cyano-methyl compounds.

in a Spanish patent (E69,09905,27.6.68 (SP) 355,900, 30.12.69) are synthesized from 2-unsubstituted 4-phenyl-1,2-dihydro-1-oxo-pyridazines and corresponding chloroacetic acid derivatives in each case methanolic potassium hydroxide 2-substituted 4-phenyl-1,2-dihydro-1-oxo-pyridazines having anti-inflammatory action described.

Another Japanese Patent (Jpn. Kokai Tokkyo Koho JP 62,252,774 (87,252,774) (CI. C07D 237/30), Nov. 4, 1987, GB Appl.

86 / 10,018.24 Apr 1986; ref. CA. 109.6531 q (1988)) describes the synthesis of 2-carbalkoxy or 2-carboxyalkyl-4-aralkyl-1,2-dihydro-1-oxo-phthalazines by reaction of the 2-unsubstituted 4-aralkyl-1,2- dihydro-1-oxo-phthalazines with bromoalkane esters and their use as aldose reductase inhibitors.

Aim of the invention

The aim of the invention is to produce such compounds from realtiv readily available starting materials in a technically relatively simple manner and with high yields.

Explanation of the essence of the invention

The object of the invention is to find a technically applicable synthesis route for the preparation of substituted 2-carbamoyl-methyl-4-phenyl-1,2,5,6-tetrahydro- and 1,2-dihydro-1-oxo-pyridazines of the general formula I. , According to the invention, the object of preparing the compounds of general formula I,

/ R "

-CH ₁ -CO -1,1

R ¹ = H, alkyl, aryl or aralkyl,

R ² = H, alkyl, aryl or aralkyl or

R 'and R ² with the heteroatom to which they are attached form a heteroaliphatic ring which may contain other heteroatoms and may be substituted;

R ³ = H, alkyl, alkoxy, NHCOCH ₃ , F, Cl, Br, I,

R ⁴ = H, alkyl,

R ⁵ = H, alkyl or R ⁴ and R ⁶ = C ₄ H ₄ may be

and the dashed line is an optional double bond,

in that 2-carbalkoxy-methyl-4-phenyl-1,2,5,6-tetrahydro or 1,2-dihydro-i-oxo-pyridazines of the general formula II,

-CH ₂ -CO-OR

wherein R ¹ , R ⁴ , R ⁶ and R ⁴ and R ⁶ and the dashed line have the abovementioned meaning and R ^e = lower alkyl C) -C ₄ , with an amine at different temperatures, usually the boiling point of the amine , be treated for different lengths.

In a second embodiment of the invention, the object can be achieved in that compounds of the general formula II in a lower alcohol, preferably Ci-C ₄ , mixed with dried ammonia gas and heated

 In a third embodiment of the invention, the object can be achieved by treating compounds of the general formula II with aqueous ammonia solution at preferably room temperature.

Ausführungsbelsplele The invention will be explained in more detail below to β embodiments. example 1

2-piperidinocarbonylmethyl-4-phenyl-1,2,5,6-tetrahydro-1-oxopyridazine I; R 'and R ¹ ·

R ³ = R ⁴ = R ⁶ = H; the dashed line is not a double bond

1,2g2-Carbethoxy-methyl-4-phenyl-1,2,5,6-tetrahydro-1-oxopyridazine (II; R ³ = R ⁴ = R ^s = H, R ^e = C ₂ H ₅ ; dashed line is not a double bond) are dissolved in 13 ml of piperidine and refluxed for 37.5 hours. After distilling off excess piperidine i. Vak. the batch is taken up in 70 ml of CHCl ₁ and shaken four times with 10 ml HCl (0.1 mol / l). The organic phase is washed with H ₂ O and dried (Na ₂ SO ₄ ). When distilling off the Lsm. remains a residue of kristallinsalbenförmlger consistency, which crystallizes on treatment with small, ice-cooled ether portions

Schmb. 139-141 ⁰ C, yield: 41%.

2- (N-methylpiperazino) carbonylmethyl-4-phenyl-1,2-dihydro-1-oxo-phthalazine I; R ¹ and R ² = N-CH ₃

Example 2 R ³ = H, R ⁴ and R ⁶ = C ₄ H ₄ ; the dashed line is a double bond

1.0 g of 2-carbethoxy-methyl-4-phenyl-1,2-dihydro-1-oxo-phthalazine (II; R ³ = H, R ⁴ and R ⁶ = C ₄ H ₄ , R ⁶ = C ₂ H ₆ the dotted line is a double bond) is refluxed in 10 ml of N-methylpiperazine for 25.5 hours. It is then stirred into 150 ml H ₂ O, the nd. filtered off, washed with H ₂ O until the dripping liquid is neutral and dried.

Schmb. 203-203.5 ° C (55% ethanol), yield: 51%. Example 3

2-Cyclohexylaminocarbonylmethyl-4- (4-fluorophenyl) -1,2-dihydro-1-oxo-phthalazine I; R ¹ »H ₁ R ²

R ³ = 4-F, R ⁴ and R ⁶ = C ₄ H ₄ ; the dashed line is a double bond

1.63 g of 2-carbethoxy-methylH- (4-fluorophenyl) -1,2-dihydro-1-oxo-phthalazine (II; R ³ = 4-F, R ⁴ and R * = C ₄ H ₄ , R * = C ₂ H ₆ ;

dashed line is a double bond) are refluxed in 16 ml of cyclohexylamine for 8 h. After cooling, the

Crystal pulp in H) OmI H ₂ O registered, the Nd. filtered off, washed with H ₂ O until the dripping liquid is neutral,

and dried.

Schmb. 259-260.5 "C (50% dioxane), yield: 81%.

Example 4 2 (2- [2,6-dichlorophenylamino] ethylamino) carbonylmethyl-4- (4-chloro-phenyl-1,2-dihydro-1-oxo-phthalazine I; R * = H,

E ²

R ³ = 4-CI, R ⁴ and R ⁶ = C ₄ H ₄ ; the dashed line is a double bond

1.71 g of 2-carbethoxy-methyl-4- (4-chlorophenyl) -1,2-dihydro-1-oxo-phthalazine (II; R ³ = 4-CI, R ⁴ and R ^s = C ₄ H ₄ , R '= C ₂ H ₆ ;

dashed line is a double bond) are kept in 17 ml of 2 (2,6-dichlorophenylamino) ethylamine for 7 h at 130-135 ° C. The compound which crystallized on cooling is sharply filtered off with suction and washed with several portions of ether to give

to remove excess diamine.

Schmb. 224-225'C (50% dioxane), yield: 71%. Example 5

2-carbamoyl-methyl-4-phenyl-1,2,5,6-tetrahydro-1-oxo-pyridazine I; R ¹ = R ² = R ³ = R ⁴ = R * = H; the dashed line is no

double bond

1,3g2-Carbethoxy-methyl-4-phenyl-1,2,5,6-tetrahydro-1-oxo-pyridazine (II; R ³ = R ⁴ = R ^s = H, R '= C ₂ H ₆ ; dashed line is not a double bond) are abs. in 25ml. C ₂ H ₆ OH dissolved and drink at room temperature for 5h. NHj gas in the batch

initiated. After standing 4tggem is heated to 30-35 ⁰ C. for 6 h and then kept at 5O ⁰ C a total of 46h. The

crystallized reaction product is filtered off with suction, the filtrate is concentrated and thereby obtained a second fraction.

Schmb. 210.5-211.5 "C (acetone), yield: 29%.

Example β

2-carbamoyl-methyl-4- (4-acetaminophenyl) -1,2,5, e -tetrahydro-1-oxopyridazine .H ₂ OI; R ¹ = R ² = HH ₂ O, R ³ = NHCOCH ₃ ,

R ⁴ = R ⁶ = H; the dashed line is not a double bond

1.59 g of 2-carbo-hydroxy-methyl-4- (4-acetaminophenyl) -1,2,5,6-tetrahydro-1-oxopyridazine (II; R ³ = NHCOCH ₃ , R ⁴ = R ⁶ = H,

R * = C ₂ Ht; the dashed line is not a double bond) are added with 10 ml of aqueous NH ₃ solution 7d Room temperature stirred. It is then filtered off with suction and washed with H ₂ O until the dripping liquid reacts neutrally,

and dried.

Schmb. 191 to 191.5 ⁰ C (38proz ethanol.), Yield: 26%.

Claims (2)

1. Process for the preparation of substituted 2-carbamoyl-methyl-4-phenyl-1,2,5,6-tetrahydro and 1,2-dihydro-1-oxo-pyridazines of the general formula I, R ¹ = H, alkyl, aryl or aralkyl, R ² = H, alkyl, aryl or aralkyl or R ¹ and R ² with the heteroatom to which they are attached form a heteroaliphatic ring containing further heteroatoms and may be substituted; R ³ = H, alkyl, alkoxy, NHCOCH ₃ , F, Cl, Br, I, R ⁴ = H, alkyl, R ⁵ = H, alkyl or R ⁴ and R ⁵ = C ₄ H ₄ may be and the dotted line is an optional double bond, characterized in that 2-carbalkoxy-methyl-4-phenyl-1,2,5,6-tetrahydro- or 1,2-dihydro-i-oxo-pyridazines of the general formula II .